World J Gastroenterol. May 14, 2014; 20(18): 5519–5526.
Published online May 14, 2014. doi: 10.3748/wjg.v20.i18.5519
PMCID: PMC4017067
Risk factors for liver-related mortality in chronic hepatitis C patients: A deceased case-living control study
In this case-control based study, the use of interferon and ribavirin for at least 12 wk was associated with a 47% decrease in liver-related mortality among CHC patients. We also found that there was a significant trend toward an increasing liver-related mortality in patients with HBsAg positivity, diabetes, hypertension, alcohol consumption and initial diagnosis at an advanced stage after controlling for potential confounders.
Chronic HCV infected cases are associated with higher mortality rates compared to non-infected individuals[23-26], which suggests that those with chronic HCV infection are at a higher risk of death and should be closely monitored. Previous studies have suggested that gender and age may influence the prognosis of CHC[3,15,27,28]; thus, the controls in the present study were matched by chronic HCV infection, gender, age and date of hospital admission to control for confounders. These variables were excluded from the statistic models. Patients with an early diagnosis of chronic HCV infection may have a better outcome, and a previous study showed that CHC-related cirrhosis increased the rate of mortality nearly four-fold compared to CHC patients without cirrhosis[15]. In our study, this rate was 2.89, while patients with HCC had a liver-related mortality 8.82 times higher than CHC patients after adjusting for confounders.
Chronic HCV infection does not have a significant impact on all-cause mortality in the first decade of infection[29]; however, liver disease progression is accelerated in the presence of cofactors such as HBV infection[2]. HBsAg positivity for longer than 6 mo is the most important indicator of chronic HBV infection, and anti-HBc positivity indicates past exposure to HBV. Previous studies have suggested that anti-HBc is not related to the prognosis of HCV infection[20,21]. In the present study, HBsAg and anti-HBc were associated with an increased rate of mortality in an unadjusted univariate analysis model; however, after adjusting for the confounders, only HBsAg remained an independent risk factor for CHC mortality. Additionally, chronic alcohol consumption in the presence of obesity and viral hepatitis could damage the liver[30]. Several studies have indicated that obesity and alcohol synergistically increase the risk of HCC and death[7,31-33]. In addition, smoking is always considered a risk factor for disease progression and poor prognosis[8,34,35], although controversial results have been reported[22]. In the present study, we found that alcohol consumption is associated with an increased risk of mortality in both univariate and multivariate analyses. In contrast, smoking was not related to mortality in either analysis. This result indicates that abstinence from habitual alcohol drinking is more directly beneficial for liver-related outcomes. Two studies have shown that diabetes was relevant to the mortality of CHC patients[6,36], and this relationship was confirmed in the present study. Furthermore, there are no data, to our knowledge, concerning the association between hypertension and the risk of HCV-related death. We found that hypertension is an independent risk factor for the increase of liver-related CHC mortality.
Antiviral therapy with interferon-α and ribavirin has been the standard of care for CHC, and among those who achieve sustained virologic response, 99% permanently remain HCV RNA-negative[37]. Many studies have suggested that interferon therapy is associated with decreased mortality, even in patients with cirrhosis[11,12,14,18,19]. There have also been reports demonstrating that the rate of progression to HCC was lowered two-fold following treatment with at least 3 × 106 IU interferon three times a week for 3 mo, regardless of the biological and virologic responses[38]. In contrast, a different study indicated that interferon-α did not affect the survival of patients with CHC[13]. However, most of these studies included very few deceased patients. In the present study, we included 144 deceased CHC inpatients for evaluation and found that patients treated with combination therapy had increased survival. To our knowledge, using this case-control study method, these are the first data showing that patients treated with interferon for at least 12 wk have reduced mortality.
The relative influence of routes of infection on the prognosis of liver disease remains controversial[22,39-42]. Additionally, whether transfusion-associated HCV and a family history of viral hepatitis are associated with a higher risk of mortality than other routes is largely unknown. The results of the present study indicate that neither the blood transfusion history nor a family history of viral hepatitis are associated with an increased risk of mortality, as indicated by both univariate and multivariate analyses.
Several limitations of the present study should be noted. First, we did not have access to information on the socioeconomic status of the subjects. It is difficult to investigate the real economic status in many patients, although a previous study showed that it impacts the prognosis of CHC patients[43]. Second, although we involved many potential factors in the statistical analysis, a number of other possible confounding variables, such as body mass index, were not included in our model because of the potential interaction with alcohol. Third, not all direct causes of death of the deceased patients were obtained from postmortem examinations due to a lack of family permission. Fourth, anti-HIV antibody status was initially included in this study; however, all cases and controls were negative for anti-HIV antibodies, and evaluating this factor was thus not possible. Fifth, HCV RNA was not determined in 16.67% (24) of cases and 1.91% (11) of controls at their last index date because HCV RNA in the case group was collected from the last admission of cases, which included some cases with bleeding varices and hepatic encephalopathy, and nearly all of the patients died shortly after this time point. At this urgent point, HCV RNA is unable to guide the treatment options; thus, HCV RNA was not determined in these 24 cases. Sixth, accurately measuring the cumulative intake of tobacco smoke and alcohol was not possible, which makes further stratification and analysis difficult. Seventh, because the initial diagnostic stage is a potential risk factors involved in assessment, it is improper to consider this a matched factor, which results in disproportionate stages between the two groups. Finally, as with any observational study, residual confounding by unmeasured factors that are different between cases and controls is possible. However, the confounding effect of medical attention could be corrected for by hospitalization, and all of the subjects in this study were inpatients.
In summary, our study demonstrates that the initial diagnostic stage of disease and comorbidities, including HBsAg seropositive status, alcohol consumption, diabetes and hypertension, are independent risk factors for liver-related mortality, whereas antiviral therapy decreases the risk of liver-related mortality in CHC patients. To our knowledge, this study is the first to investigate the risk of CHC mortality using a deceased case-living control study design and the first to indicate that hypertension may be a risk and antiviral therapy for a period of at least 12 wk may be beneficial for liver-related CHC mortality. We suggest that physicians should consider the above-mentioned conditions during disease evaluation.
PMID:24833882 [PubMed - in process]
PMCID:PMC4017067
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